Molecular genetics of ornithine decarboxylase in human tumor cells

As the molecular biology of mammalian ornithine decarboxylase is coming of age, more and more interesting features of this unique protein are being uncovered. Ornithine decarboxylase belongs to those 20 or so enzymes or binding proteins, the genes for which are easily amplified under suitable selection pressure. This also applies to the human enzyme. Gene amplification of ornithine decarboxylase is not the only means to acquire resistance to inhibitors of the enzyme, as its overproduction can occur through an enhanced transcription or even through a more efficient translation of normal mRNA amounts. The resistance in human tumors can likewise be acquired by activating other enzymes, such as arginase. In contrast to the multigene family in mouse, it appears that in the human genome only two ornithine decarboxylase genes are present mapping to the chromosomes 2 and 7. Out of these, at least the sequences in the short arm of chromosome 2 are transcriptionally active and amplifiable. Human ornithine decarboxylase also belongs to those proteins which show a positive correlation between gene hypomethylation and expression. The genes of human ornithine decarboxylase are methylated to varying extents and distinct hypomethylation is seen in certain malignant cells, most notably human lymphatic leukemia cells. The human ornithine decarboxylase gene is easily transferrable into other mammalian cells in which it is efficiently expressed. Some indirect evidence seems to indicate that overproduction of ornithine decarboxylase may confer a growth advantage to mammalian cells. A further piece of information suggesting an important role for the enzyme is the fact that the structure of the ornithine decarboxylase gene is extremely well conserved during evolution. This does not apply only to the coding region but also to the overall organization of the gene itself.